One promising new therapy for Parkinson's Disease (PD) involves the replacement of degenerated nigrostriatal neurons with those derived from transplanted fetal mesencephalic tissue. Although this approach has often yielded remarkable recovery of function in rats and monkeys, results in clinical trials with PD patients have been less consistent. At issue, is the relative inability to standardize a number of critical factors in human fetal transplants, including the age, type, number and integrity of cells being grafted. Consequently, finding more reliable sources of dopaminergic (DA) tissue for transplantation has become increasingly important. One direction has been to search for a line of readily available, well-characterized, continually self-renewing stem or precursor cells that possess the capacity to differentiate, ideally spontaneously and without need of genetic manipulation, into DA neurons, thus providing an inexhaustible and uniform source of replacement tissue. Towards this end, our preliminary findings demonstrate that grafts of embryonic mouse neural stem cells of the C17.2 cell can differentiate exclusively into neurons, which in a majority of cases, can express DA traits when transplanted into the brain of a Parkinsonian rat. In addition, we now have available two human NSC lines (HNSC.100 and HSP-2) which are being studied in vitro and in rat models of PD. Therefore, the goal of the present proposal is to move a step closer to the clinic by testing the utility of both mouse and human stem cells in a non-human primate model of PD. Our specific goals for this proposal are twofold: 1) Determine whether mouse NSCs behave in a primate model as they do in a rat model of PD; and 2) Determine whether human NSCs also differentiate, integrate and function as DA neurons when transplanted into the MPTP-treated monkey. The ultimate goal of this research program is a fuller understanding of the cellular and molecular processes regulating the differentiation of DA traits in stem cells and application of that knowledge to transplantation strategies for the treatment of Parkinson's Disease.